Despite the fact that all individuals with sickle cell anemia (SS) have the identical genetic defect (homozygous beta 6 glu to val), there is a wide variation in clinical severity. While clinicians have long been aware of this variability, it was the epidemiologic data amassed by the NHLBI's Cooperative Study of Sickle Cell Disease (CSSCD) that allowed objective measurement of this variability and identification of key risk factors for severity. In this proposal we focus on one of the key risk factors for severity identified by the CSSCD - baseline white blood cell count (baseline WBC). This initially unanticipated risk factor is becoming more obviously relevant as new investigations into the pathophysiology of the disease increasingly emphasize the importance of white cells and inflammation. At the same time, baseline WBC and other markers of inflammation are emerging as risk factors for mortality in the general population, making the exploration of genetic determinants of baseline WBC of interest not only to the SS population, but also to the population at large. Our strategy for locating the genes that are responsible for the variability in baseline WBC involves three unique populations: inbred strains of mice (Jackson Labs, Bar Harbor), baboon pedigrees (Southwest Foundation for Biomedical Research, San Antonio), and nuclear and extended families of ~300 probands with SS (Boston, Creteil). The animals will be useful in determining quantitative trait loci (QTLs) and ultimately individual genes that influence baseline WBC. The SS probands and their families will allow quantification of the relative importance of genetic and environmental modifiers of baseline WBC in the probands (SS), as well as their normal heterozygous (AS) and unaffected (AA) relatives. Genotyping, and phenotyping using baseline WBC and more specific markers of inflammation (e.g. cytokines, adhesion molecules, hematopoietic growth factors) in these families will allow not only QTL mapping and gene identification, but also an analysis of how genetically interrelated the inflammatory markers are. We anticipate that these studies will provide new insights into the genetics of inflammation that will be of benefit to patients with SS as well as the general population of African heritage. In addition, the data and sample resource we will create is designed to continue to answer questions well beyond the inflammation issue that we focus on in this proposal.